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ES2496771T3 - Rifaximin powder, process for preparation thereof and controlled release compositions containing said rifaximin useful for obtaining a long lasting effect - Google Patents

Rifaximin powder, process for preparation thereof and controlled release compositions containing said rifaximin useful for obtaining a long lasting effect Download PDF

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Publication number
ES2496771T3
ES2496771T3 ES11714663.9T ES11714663T ES2496771T3 ES 2496771 T3 ES2496771 T3 ES 2496771T3 ES 11714663 T ES11714663 T ES 11714663T ES 2496771 T3 ES2496771 T3 ES 2496771T3
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rifaximin
preparation
powder
controlled release
obtaining
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Giuseppe Claudio Viscomi
Paola Maffei
Vittoria Lauro
Miriam Barbanti
Donatella Confortini
Dario Braga
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Alfa Wasserman SpA
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/16—Peri-condensed systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

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Abstract

Un proceso para la preparación de polvo de rifaximina que tiene un espectro de difracción de rayos X correspondiente a una forma amorfa, que tiene un tamaño de partícula entre 40 y 120 micrómetros en un porcentaje de 90% de las partículas totales como se determina utilizando un analizador de tamaño de partícula Beckman- Coulter LS100 Q equipado con una celdilla de micro-volumen, y una densidad a granel entre 0,1 y 0,5 g/ml como se determina utilizando un matraz aforado de 10 ml, caracterizado por los pasos de: a) solubilización de rifaximina cristalina o amorfa, o sus mezclas, en disolventes orgánicos o sus mezclas; b) pulverización de dicha solución en un aparato de lecho fluido a una presión comprendida entre 0,5 y 2,5 bar en una corriente de aire templado; c) secado de la rifaximina sólida hasta peso constante a una temperatura comprendida entre 20ºC y 120ºC.A process for the preparation of rifaximin powder having an X-ray diffraction spectrum corresponding to an amorphous form, which has a particle size between 40 and 120 micrometers in a percentage of 90% of the total particles as determined using a Beckman-Coulter LS100 Q particle size analyzer equipped with a micro-volume cell, and a bulk density between 0.1 and 0.5 g / ml as determined using a 10 ml volumetric flask, characterized by the steps from: a) solubilization of crystalline or amorphous rifaximin, or mixtures thereof, in organic solvents or mixtures thereof; b) spraying said solution in a fluid bed apparatus at a pressure between 0.5 and 2.5 bar in a stream of warm air; c) drying of the solid rifaximin to constant weight at a temperature between 20 ° C and 120 ° C.

Description

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TABLA 1 TABLE 1

Comparación de Valores PK perro-hombre que recibieron rifaximina -Valores medios ± error estándar Comparison of PK values dog-man who received rifaximin -Average values ± standard error

Cmax (ng/ml) Cmax (ng / ml)
Tmax (h) AUC0-24h (ng.h/ml) Tmax (h) AUC0-24h (ng.h / ml)

Valores observados en perros después de administración de 100 mg/kg (Tabla 14) correspondiente a una HED de 54,4 mg/kg Values observed in dogs after administration of 100 mg / kg (Table 14) corresponding to an HED of 54.4 mg / kg
1044,1 ± 588,46 2 2854,31 ± 1489,87 1044.1 ± 588.46 2 2854.31 ± 1489.87

Valores calculados en humanos reducidos proporcionalmente a la dosis de 2,9 mg/kg Values calculated in humans reduced proportionally to the dose of 2.9 mg / kg
56,1 ± 31,63 ND 143,4 ± 80,10 56.1 ± 31.63 ND 143.4 ± 80.10

Valores observados en humanos después de administración de tabletas de 200 mg correspondientes a 2,9 mg/kg Values observed in humans after administration of 200 mg tablets corresponding to 2.9 mg / kg
3,70 ± 0,55 1,04 11,47 ± 2,35 3.70 ± 0.55 1.04 11.47 ± 2.35

Por comparación de los valores de los parámetros PK calculados a 2,9 mg/kg HED obtenidos sobre la base del experimento en perros con los observados en humanos, cuando está comprendida en la preparación farmacéutica By comparison of the values of the PK parameters calculated at 2.9 mg / kg HED obtained on the basis of the experiment in dogs with those observed in humans, when included in the pharmaceutical preparation

5 del Ejemplo 3 la rifaximina del Ejemplo 1, se deduce que la nueva composición, por combinación del efecto de la forma de rifaximina y la composición farmacéutica, como se describe en el Ejemplo 3, reduce los niveles de biodisponibilidad de rifaximina en sangre si se compara con una administración directa de la rifaximina preparada por el método de secado por pulverización, como se describe en el Ejemplo 1. 5 of Example 3 the rifaximin of Example 1, it follows that the new composition, by combination of the effect of the rifaximin form and the pharmaceutical composition, as described in Example 3, reduces the bioavailability levels of rifaximin in blood if compares with a direct administration of rifaximin prepared by the spray drying method, as described in Example 1.

La composición farmacéutica de las tabletas obtenidas conforme al Ejemplo 3 exhibe de hecho el resultado The pharmaceutical composition of the tablets obtained according to Example 3 actually exhibits the result.

10 inesperado derivado de la combinación de parámetros que actúan en direcciones opuestas: la rifaximina producida por el proceso de secado por pulverización conduce a rifaximina más soluble con un posible aumento de la biodisponibilidad, mientras que la composición y la forma farmacéutica en tabletas y el método de producción limitan el nivel de absorción, dando como resultado una liberación controlada. Unexpected derived from the combination of parameters that act in opposite directions: rifaximin produced by the spray drying process leads to more soluble rifaximin with a possible increase in bioavailability, while the composition and pharmaceutical form in tablets and the method of production limit the level of absorption, resulting in a controlled release.

La evidencia de la propiedad de la formulación se muestra en las Figuras 1 y 2, que consignan los valores de Evidence of the property of the formulation is shown in Figures 1 and 2, which record the values of

15 concentraciones en plasma en dos individuos voluntarios diferentes, calculadas después de administraciones repetidas de formulaciones en tabletas que contienen la rifaximina preparada conforme al Ejemplo 3 si se compara con el producto comercial Normix®. 15 plasma concentrations in two different voluntary individuals, calculated after repeated administrations of tablet formulations containing rifaximin prepared according to Example 3 if compared with the commercial product Normix®.

La comparación de los dos perfiles en los dos individuos voluntarios sanos tratados con la formulación de la presente invención demuestra que en ningún intervalo de tiempo a lo largo de la terapia total se exhibe cantidad The comparison of the two profiles in the two healthy voluntary individuals treated with the formulation of the present invention demonstrates that in no time interval throughout the total therapy amount is exhibited.

20 alguna de rifaximina detectable en el plasma, mientras que los pacientes tratados con las tabletas disponibles comercialmente que contenían rifaximina (Normix®) exhiben concentraciones en plasma de rifaximina no detectables analíticamente. 20 some of rifaximin detectable in plasma, while patients treated with commercially available tablets containing rifaximin (Normix®) exhibit plasma concentrations of rifaximin not analytically detectable.

Por tanto, un aspecto de la invención es una composición capaz de liberar rifaximina en condiciones de liberación predecible y controlada. Dicha composición comprende un polvo de rifaximina que tiene la característica Therefore, one aspect of the invention is a composition capable of releasing rifaximin under predictable and controlled release conditions. Said composition comprises a rifaximin powder having the characteristic

25 morfológica arriba descrita, y que se obtiene por un proceso de secado por pulverización. 25 morphological described above, and which is obtained by a spray drying process.

14 14

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TABLA 2 TABLE 2

Parámetros del proceso Process parameters
Precalentamiento Pulverización Secado Preheating Spray Drying

Volumen del aire de entrada Inlet air volume
800 ± 200 m3/h 800 ± 200 m3/h 800 ± 200 m3/h 800 ± 200 m3 / h 800 ± 200 m3 / h 800 ± 200 m3 / h

Temperatura del aire de entrada Inlet air temperature
90 ± 10°C 90 ± 10°C 60 ± 5°C 90 ± 10 ° C 90 ± 10 ° C 60 ± 5 ° C

Presión de pulverización Spray pressure
0,7 ± 0,2 bar 0.7 ± 0.2 bar

Tasa de pulverización Spray rate
50 -380 g/min 50-380 g / min

Temperatura del producto Product temperature
55 -70°C 50 ± 2°C 55 -70 ° C 50 ± 2 ° C

El polvo de rifaximina obtenido se analiza por espectroscopia de rayos X, espectrometría 13C-NMR y espectroscopia IR, y es estable a una temperatura de 40ºC ± 2 con una humedad relativa de 75% hasta 3 meses. The rifaximin powder obtained is analyzed by X-ray spectroscopy, 13C-NMR spectrometry and IR spectroscopy, and is stable at a temperature of 40 ° C ± 2 with a relative humidity of 75% up to 3 months.

5 El espectro de difracción de rayos X se consigna en la Figura 3, que muestra halo-picos que tienen máximos a 7,75º ± 1,02, 14,54º ± 0,2 y 18,33 ± 0,2, 2θ. 5 The X-ray diffraction spectrum is reported in Figure 3, which shows halo-peaks that have maximums at 7.75º ± 1.02, 14.54º ± 0.2 and 18.33 ± 0.2.2θ.

El espectro de difracción de rayos X se obtiene por la geometría Bragg-Brentano en las condiciones siguientes: tubo de rayos X: cobre; radiación: K(α1), K(α2); tensión de la corriente del generador: KV 40, mA 40; monocromador: grafito; tamaño de paso 0,02; tiempo de paso: 1,25 segundos; valor angular inicial y final de 2θ: 3,0º-30,0 ± 0,2d. The X-ray diffraction spectrum is obtained by Bragg-Brentane geometry under the following conditions: X-ray tube: copper; radiation: K (α1), K (α2); generator current voltage: KV 40, mA 40; monochromator: graphite; step size 0.02; step time: 1.25 seconds; initial and final angular value of 2θ: 3.0º-30.0 ± 0.2d.

10 La Figura 4 muestra el espectro 13C-NMR obtenido por el instrumento Varian 400 a 100,56 MHz, por fusión de la muestra de cloroformo que tiene una pureza mayor que 99,8% y que contiene tetrametilsilano como patrón interno. 10 Figure 4 shows the 13C-NMR spectrum obtained by the Varian 400 instrument at 100.56 MHz, by fusion of the chloroform sample having a purity greater than 99.8% and containing tetramethylsilane as internal standard.

La Figura 5 muestra el espectro IR obtenido con el equipo Spectrum One, Perkin Elmer, utilizando una dispersión al 0,5% de rifaximina en bromuro de potasio, y registrándose el espectro a frecuencias de 4000 a 450 cm-1 . Figure 5 shows the IR spectrum obtained with the Spectrum One, Perkin Elmer, using a 0.5% dispersion of rifaximin in potassium bromide, and the spectrum being recorded at frequencies of 4000 to 450 cm -1.

La rifaximina así obtenida es estable, como se muestra en la Tabla 3. The rifaximin thus obtained is stable, as shown in Table 3.

15 TABLA 3 15 TABLE 3

Rifaximina obtenida por el Ejemplo 1 y mantenida a T = 40°C ± 2°C con humedad relativa = 75 ± 5% Rifaximin obtained by Example 1 and maintained at T = 40 ° C ± 2 ° C with relative humidity = 75 ± 5%

Test Test
Criterios de aceptación T0 1 mes 3 meses Criteria of acceptance T0 1 month 3 months

Descripción Description
Polvo amarillo anaranjado Polvo amarillo anaranjado Polvo amarillo anaranjado Polvo amarillo anaranjado Orange yellow powder Orange yellow powder Orange yellow powder Orange yellow powder

Espectro FT-IT FT-IT spectrum
Cumple con con el estándar Cumple con con el estándar Cumple con con el estándar Cumple con con el estándar Complies with the standard Complies with the standard Complies with the standard Complies with the standard

Espectro de difracción de rayos X X-ray diffraction spectrum
Cumple con una forma amorfa de rifaximina Cumple con una forma amorfa de rifaximina Cumple con una forma amorfa de rifaximina Cumple con una forma amorfa de rifaximina Complies with an amorphous form of rifaximin Complies with an amorphous form of rifaximin Complies with an amorphous form of rifaximin Complies with an amorphous form of rifaximin

Contenido de agua (Karl Fisher) Water content (Karl Fisher)
≤ 8% 2,2% 4,9% 5,4% ≤ 8% 2.2% 4.9% 5.4%

Impurezas totales Total impurities
≤ 2,0% 0,51% 0,54% 0,95% ≤ 2.0% 0.51% 0.54% 0.95%

16 16

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La densidad de la rifaximina obtenida por secado por pulverización es 0,257 g/ml, y la densidad de la rifaximina obtenida por molienda es 0,327 g/ml. The density of rifaximin obtained by spray drying is 0.257 g / ml, and the density of rifaximin obtained by milling is 0.327 g / ml.

e) Superficie Específica (BET) e) Specific Surface (BET)

Para la determinación de las áreas de superficie baja se utilizó una técnica de gas fluyente. Los análisis se To determine the low surface areas, a flowing gas technique was used. The analyzes are

5 realizaron utilizando nitrógeno gaseoso sobre 300 mg de muestra secada a vacío, aumentado la temperatura desde 25ºC a 100ºC con una tasa de calentamiento de 10ºC/min. La superficie específica de la rifaximina obtenida por secado por pulverización está comprendida entre 0,01 y 5 m2/g, y la superficie específica de la rifaximina obtenida por molienda está comprendida entre 6 y 12 m2/g. 5 performed using gaseous nitrogen on 300 mg of vacuum dried sample, increasing the temperature from 25 ° C to 100 ° C with a heating rate of 10 ° C / min. The specific surface area of rifaximin obtained by spray drying is between 0.01 and 5 m2 / g, and the specific surface area of rifaximin obtained by milling is between 6 and 12 m2 / g.

f) Solubilidad f) Solubility

10 500 mg de cada preparación de rifaximina consignada en el Ejemplo 1 y rifaximina obtenida por molienda, respectivamente, se suspendieron por separado en 750 ml de una solución tampón acuosa de fosfatos, pH 6,8, temperatura 30 ± 0,5ºC. 10 500 mg of each preparation of rifaximin reported in Example 1 and rifaximin obtained by milling, respectively, were suspended separately in 750 ml of an aqueous phosphate buffer solution, pH 6.8, temperature 30 ± 0.5 ° C.

Las soluciones que contienen rifaximina suspendida se agitan por medio de un agitador de barrido durante 150 minutos a la tasa de agitación de 250 rpm. Las muestras tomadas a intervalos de 5 minutos durante la primera hora The solutions containing suspended rifaximin are stirred by means of a sweeping stirrer for 150 minutes at the stirring rate of 250 rpm. Samples taken at 5 minute intervals during the first hour

15 y a intervalos de 15 minutos en el tiempo restante se analizan en HPLC después de filtración. Los resultados se consignan en la Tabla 5. 15 and at intervals of 15 minutes in the remaining time are analyzed in HPLC after filtration. The results are recorded in Table 5.

TABLA 5 TABLE 5

Solubilidad a lo largo del tiempo de la preparación de rifaximina Solubility over time of rifaximin preparation

Concentración (mg/l) Concentration (mg / l)

Tiempo (min) Time (min)
Secado por Pulverización Molienda Spray Drying Grinding

5 5
14,4 10,8 14.4 10.8

10 10
30,2 14,3 30.2 14.3

15 fifteen
44,0 15,9 44.0 15.9

20 twenty
47,0 16,7 47.0 16.7

25 25
38,0 16,9 38.0 16.9

30 30
28,7 16,7 28.7 16.7

35 35
22,4 16,1 22.4 16.1

40 40
17,7 15,4 17.7 15.4

4S 4S
14,9 14,8 14.9 14.8

50 fifty
13,1 14,0 13.1 14.0

55 55
11,8 13,5 11.8 13.5

60 60
11,0 12,9 11.0 12.9

75 75
9,9 12,1 9.9 12.1

90 90
9,5 10,9 9.5 10.9

105 105
9,3 9,8 9.3 9.8

18 18

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Claims (1)

imagen1image 1 imagen2image2
ES11714663.9T 2010-03-05 2011-03-04 Rifaximin powder, process for preparation thereof and controlled release compositions containing said rifaximin useful for obtaining a long lasting effect Active ES2496771T3 (en)

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PCT/IB2011/050933 WO2011107970A2 (en) 2010-03-05 2011-03-04 Rifaximin powder, process for preparing the same and controlled release compositions containing said rifaximin useful for obtaining a long-lasting effect.

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